The composition of gut microbiota has been associated with host metabolic phenotypes (Ley et al., 2006) and transfer of ‘obese’ microbiota can induce adiposity (Turnbaugh et al., 2006) and hyperphagia (Vijay-Kumar et al., 2010), suggesting that gut microbiota may influence host feeding behavior. Although the mechanisms underlying effects of gut bacteria on host appetite are unknown, it is likely that they may use host molecular pathways controlling food intake.
The current model of food intake control implicates gut-derived hunger and satiety hormones signaling to several brain circuitries regulating homeostatic and hedonic aspects of feeding (Berthoud, 2011; Inui, 1999; Murphy and Bloom, 2006). Prominent amongst these are the anorexigenic and orexigenic pathways originating from the hypothalamic arcuate nucleus (ARC) that include the proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons, respectively, relayed in the paraventricular nucleus (PVN) (Atasoy et al., 2012; Cowley et al., 1999; Garfield et al., 2015; Shi et al., 2013). The ARC and PVN pathways converge in the lateral parabrachial nucleus which sends anorexigenic projections to the central amygdala (CeA), expressing calcitonin gene-related peptide (CGRP) (Carter et al., 2013; Garfield et al., 2015).
Putative mechanisms of gut microbiota effect on host control of appetite may involve its energy harvesting activities (Turnbaugh et al., 2006) and production of neuroactive transmitters and metabolites (Dinan et al., 2015; Forsythe and Kunze, 2013; Sharon et al., 2014). The inventors evidenced an implication of bacterial proteins which act directly on appetite-controlling pathways locally in the gut or systemically. In fact, several bacterial proteins have been shown to display sequence homology with peptide hormones regulating appetite (Fetissov et al., 2008), and recently ClpB protein produced by gut commensal Escherichia coli (E. coli) was identified as an antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) (Tennoune et al., 2014). α-MSH is a POMC-derived neuropeptide playing a key role in signaling satiation by activation of the melanocortin receptors 4 (MC4R) (Cone, 2005). Although MC4R-mediated α-MSH anorexigenic effects have been mainly ascribed to its central sites of actions (Mul et al., 2013), a recent study showed that activation of the MC4R in the gut enteroendocrine cells stimulates release of satiety hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) (Panaro et al., 2014). Thus gut bacteria-derived α-MSH-like molecules can directly act on enteroendocrine cells synthetizing satiety hormones.